3-193593380-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_130837.3(OPA1):c.3G>A(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OPA1 NM_130837.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.83

Genes affected

OPA1 (HGNC:8140): (OPA1 mitochondrial dynamin like GTPase) The protein encoded by this gene is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. The encoded protein localizes to the inner mitochondrial membrane and helps regulate mitochondrial stability and energy output. This protein also sequesters cytochrome c. Mutations in this gene have been associated with optic atrophy type 1, which is a dominantly inherited optic neuropathy resulting in progressive loss of visual acuity, leading in many cases to legal blindness. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_130837.3 (OPA1) was described as [Likely_pathogenic] in ClinVar as 2504752
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-193593380-G-A is Pathogenic according to our data. Variant chr3-193593380-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1184499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-193593380-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-193593380-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPA1	NM_130837.3	c.3G>A	p.Met1?	start_lost	1/31	ENST00000361510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPA1	ENST00000361510.8	c.3G>A	p.Met1?	start_lost	1/31	5	NM_130837.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395440 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 688144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genomics England Pilot Project, Genomics England

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

This sequence change affects the initiator methionine of the OPA1 mRNA. The next in-frame methionine is located at codon 125. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with autosomal dominant optic atrophy (PMID: 28125838, 31500643, 32141364, 34758253). ClinVar contains an entry for this variant (Variation ID: 1184499). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0059	T;.;.;T;T;.;T;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Benign	-0.74	N;N;N;N;N;N;N;.;N;.
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;.
Sift4G	Benign	0.073	T;T;T;T;T;T;D;.;T;.
Polyphen		0.53	P;.;.;P;P;.;.;.;.;.
Vest4		0.87
MutPred		0.99		Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);
MVP		0.97
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.94
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1724946838; hg19: chr3-193311169;